Asian citrus psyllid, Diaphorina citri Kuwayama (Hemiptera: Liviidae), transmits the causal pathogen of huanglongbing and is a global pest of citrus. D. citri populations exhibit resistance to multiple insecticide modes of action in areas where these chemicals have been overused. We performed genome‐wide transcriptional analysis for two field populations of D. citri (Wauchula and Lake Alfred, Florida, USA) that exhibit 1300‐fold resistance to the neonicotinoid insecticide, thiamethoxam, and compared it to that of susceptible psyllids collected from the same area and without imposed selection. The Lake Alfred population responded to insecticide resistance by up‐regulation of 240 genes and down‐regulation of 148 others. The Wauchula population exhibited similar patterns to the Lake Alfred population with up‐regulation of 253 genes and down‐regulation of 115 others. Gene Ontology annotation associated with cellular processes, cell, and catalytic activity were assigned to differentially expressed genes (DEGs). The DEGs from Lake Alfred and Wauchula populations were mapped to Kyoto Encyclopedia of Gene and Genomes pathways and implicated enrichment of metabolic pathways, oxidative phosphorylation, extracellular matrix‐receptor interaction, terpenoid backbone biosynthesis, and insect hormone biosynthesis in the resistant populations. Up‐regulation of 60s ribosomal proteins, UDP‐gluscoyltransferases, cytochrome c oxidases, and CYP and ABC transporters among thiamethoxam‐resistant D. citri implicates a broad array of novel and conventionally understood resistance mechanisms.